This article has Open Peer Review reports available.
Unusual presentation of a severely ill patient having severe fever with thrombocytopenia syndrome: a case report
© The Author(s). 2017
Received: 28 November 2016
Accepted: 27 December 2016
Published: 3 February 2017
Severe fever with thrombocytopenia syndrome is an emerging infectious disease caused by a novel phlebovirus belonging to the family Bunyaviridate. Emergence of encephalitis/encephalopathy during severe fever with thrombocytopenia syndrome progression has been identified as a major risk factor associated with a poor prognosis. Here we report the case of a severely ill patient with severe fever with thrombocytopenia syndrome virus-associated encephalitis/encephalopathy characterized by a lesion of the splenium, which resolved later.
A 56-year-old Japanese man presented with fever and diarrhea, followed by dysarthria. Diffusion-weighted magnetic resonance imaging demonstrated high signal intensity in the splenium of the corpus callosum. The severe fever with thrombocytopenia syndrome virus genome was detected in our patient’s serum, and the clinical course was characterized by convulsion, stupor, and hemorrhagic manifestations, with disseminated intravascular coagulation and hemophagocytic lymphohistiocytosis. Supportive therapy not including administration of corticosteroids led to gradual improvement of the clinical and laboratory findings, and magnetic resonance imaging demonstrated resolution of the splenial lesion. The serum severe fever with thrombocytopenia syndrome viral copy number, which was determined with the quantitative reverse-transcription polymerase chain reaction, rapidly decreased despite the severe clinical course. Our patient’s overall condition improved, allowing him to be eventually discharged.
Patients with encephalitis/encephalopathy due to severe fever with thrombocytopenia syndrome virus infection may have a favorable outcome, even if they exhibit splenial lesions and a severe clinical course; monitoring the serum viral load may be of value for prediction of outcome and potentially enables the avoidance of corticosteroids to intentionally cause opportunistic infection.
Severe fever with thrombocytopenia syndrome (SFTS) is a recently identified infectious disease endemic to China, South Korea, and Japan, with a reported fatality rate between 12% and 30% . The emergence of central nervous system (CNS) manifestations during SFTS progression has been identified as a major risk factor for mortality .
The presence of reversible lesions that involve the splenium of the corpus callosum (SCC) has been reported in patients with a broad spectrum of diseases and conditions and is referred to as reversible splenial lesion syndrome (RESLES) . The magnetic resonance imaging (MRI) features of RESLES include reversible lesions limited to the splenium of the corpus callosum (SCC) or to the SCC and frontal white matter; hyperintense signals on T2-weighted images (T2WI), fluid-attenuated inversion recovery (FLAIR) images and diffusion-weighted images (DWI); with low apparent diffusion coefficient (ADC) values and hypo- or iso-intense signals on T1-weighted imaging (T1WI) sequences with no contrast enhancement [4, 5].
The exact pathophysiology and the specific site predilection of transient SCC lesions in RESLES are not understood. It has been suggested that transient SCC lesions likely reflect rapidly resolving intramyelinic edema or the influx of inflammatory cells and macromolecules, combined with related cytotoxic edema and hypotonic hyponatremia, which result from infection [6–8].
Here we report the case of a severely ill patient with SFTS virus-associated encephalitis/encephalopathy in whom follow-up magnetic resonance imaging (MRI) demonstrated a lesion in the SCC. This lesion eventually resolved, and our patient made a complete clinical recovery within a few weeks. Analysis of the SFTS viral load in our patient’s serum during hospitalization demonstrated a rapid decrease.
A 56-year-old Japanese man, who had been engaged in agricultural activities in a hilly rural area of Japan, presented to a local hospital in August, with a 2-day history of fever and diarrhea. Dysarthria and irritability were also evident. He had long-standing diabetes mellitus that had been well controlled with metformin. His vital signs were normal except for pyrexia (temperature of 38.5 °C).
On admission, our patient’s Glasgow score (GCS) was 12 (E3, V3, M6), and he showed limb tremor and scanning speech. A tick bite wound was observed on the anterior aspect of his right ankle.
Blood tests showed leukopenia with a shift to the left, 2.8 × 109/L (normal range: 4.0–9.0) with 48% bands and 1% of atypical lymphocyte.
The other laboratory tests yielded the following results: platelet count, 59 × 109/L (150–450); and hemoglobin, 14.7 g/dL (12–16); C-reactive protein, 1.51 mg/dL (0–0.3); AST, 159 U/L (13–33); ALT, 59 U/L (8–42); LDH, 429 U/L (100–200); creatinine, 1.21 mg/dL (0.36–1.06); CK, 2559 U/L (62–287); serum ferritin, 1980 U/mL (122–496); and sodium levels, 129 mmol/L (135–149).
These laboratory findings fulfilled the diagnostic criteria for acute disseminated intravascular coagulation (DIC)  and the clinical diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH) was made by the revised diagnostic criteria including fever, bicytopenia, hepatitis, high level of serum ferritin and sIL-2R, and hemophagocytosis in bone marrow .
Thereafter, our patient’s CNS manifestations deteriorated, and he exhibited convulsion and stupor as well as hemorrhagic manifestations, such as gingival bleeding and melena. Lumbar puncture was not performed due to DIC. However, a follow-up DW brain MRI scan on the 5th day of illness demonstrated complete disappearance of the SCC signal enhancement (Fig. 1c).
Laboratory findings of the presented case of severe fever with thrombocytopenia syndrome (SFTS)
Days after illness onset
Urine protein (mg/day)
The SFTS viral load in serum samples collected from our patient, on days 1, 3, 5, 7, 11, and 14 after illness onset were determined by quantitative RT-PCR (qRT-PCR), as described previously [11, 12]. On admission, there had been 2.8 × 105 copies/mL, but the viral load rapidly decreased during the remaining period of hospitalization (Fig. 2).
We have reported the case of a severely ill patient with SFTSV-associated encephalitis/encephalopathy in whom an SCC lesion was detected, but showed spontaneous resolution. The presence of a reversible SCC lesion has been reported in patients with a broad spectrum of diseases and conditions, and is referred to as RESLES . Infection is the most common cause of this abnormality. To the best of our knowledge, this is the first reported case of RESLES in a patient with SFTSV infection.
The common neurological symptoms of RESLES associated with encephalitis/encephalopathy may include delirium, short-term disturbance of consciousness, and seizures, but usually patients show complete recovery without neurological sequelae after a short disease course [13, 14]. Although CNS manifestations are common in patients with SFTS, signs of severe CNS disturbance, such as coma and convulsion, are thought to be major clinical indicators of poor prognosis . An epidemiologic study of 538 patients with SFTS revealed that 19.1% of them developed encephalitis and 44.7% of the 19.1% died .
In the present case, it was not clear whether the severe CNS disturbance was due to the severe clinical course of SFTS itself or the SCC lesion that developed secondarily. Achalia et al. speculated that the prognosis of RESLES may depend on the underlying disorder and not on other factors . The worsening CNS manifestations, hemorrhagic manifestations, and laboratory data in the present patient were consistent with severe SFTSV infection. HLH may also have contributed to disease severity and clinical outcome . HLH results from excessive activation of the immune system, leading to uncontrolled cytokine release. Although the mechanism responsible for reversible SCC lesions is unknown, Tada et al. postulated that intra-myelinic edema or an inflammatory infiltrate might account for the transient decrease in the ADC value . In the present case, we suspect that an inflammatory infiltrate caused by cytokine cascades under conditions of HLH may have been involved in the pathogenesis of the reversible SCC lesion.
SFTS patients with severe complications such as secondary HLH often receive corticosteroids, which repress immune functions. SFTS patients are somewhat immunodeficient  or have damaged immune systems with low levels of CD3+ and CD4+ T lymphocytes [19, 20], which may be due to a viral-associated hemophagocytic syndrome. Such immunodeficiency has an important role in disease progression, disease severity, and clinical outcome. Therefore, the administration of corticosteroids for the treatment of HLH, is controversial, because it sometimes worsens the infectious disease status including causing opportunistic infections. In fact, some lethal SFTS cases have involved patients with a history of early treatment with dexamethasone. In particular, two autopsy cases of Japanese SFTS patients, who received corticosteroids for hemophagocytosis, complicated by Aspergillus or Mucor infection were reported . It is noteworthy that in the patient with Aspergillus infection, the thrombocytopenia and other organ pathologies were improving, although the aggressive pulmonary aspergillosis exacerbated the clinical course and resulted in death in the patient. Because the use of corticosteroids in severely ill SFTS patients may be possible to induce opportunistic infections, a prospective study is needed to evaluate the efficacy of corticosteroid therapy.
It appears that SFTS viral load is related to morbidity . It has been reported that the SFTS viral load in acute-phase peripheral blood samples was significantly higher in patients who died than in those who survived, and that a high titer of ≥108 copies/mL led to fatal outcomes [18, 22]. The mean viral load in the survivor group was 105 copies/mL, which were consistent with the findings reported by Zhang et al. . Thus, there is a possibility that in this case report the serum SFTS viral load elevation on admission we see, which was equivalent to that in the survivors reported by Zhang et al., contributed to the favorable outcome, even though the patient was severely ill. Therefore, a rapid decline in the viral load revealed by periodic monitoring may be useful in predicting the outcome in severely ill patients with SFTS.
The present case suggests that SFTSV infection can trigger reversible SCC lesions. Even if patients show unexpectedly severe and prolonged CNS disturbance during SFTS progression, monitoring of the serum SFTS viral load in the acute phase may reveal a rapid decline that is predictive of a favorable outcome and may enable the avoidance of the use of corticosteroids, which potentially cause opportunistic infection.
There are no funding sources to declare.
Availability of data and materials
No specific systems, including software or databases, were used.
Relevant clinical data are provided in the text and any further information required can be supplied if required.
MK, HH, M Shimojima, and M Saijo designed the study. MK and M Saijo drafted the manuscript. MK, MM, H Shikata, KA, and H Shinomiya contributed to the diagnosis and treatment. TS and HH performed the experiment and contributed to the acquisition, analysis, and interpretation of data. H Shikata reviewed and edited the manuscript. MK and M Saijo reviewed and supervised the manuscript. All of the authors approved the final version of the manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Ethics approval and consent to participate
This study was approved by the ethics committee of the Uwajima City Hospital (Approval number: 1610-240).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Yu XJ, Liang MF, Zhang SY, Liu Y, Li JD, Sun YL, et al. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med. 2011;364(16):1523–32.View ArticlePubMedPubMed CentralGoogle Scholar
- Gai ZT, Zhang Y, Liang MF, Jin C, Zhang S, Zhu CB, et al. Clinical progress and risk factors for death in severe fever with thrombocytopenia syndrome patients. J Infect Dis. 2012;206(7):1095–102.View ArticlePubMedGoogle Scholar
- Renard D, Castelnovo G, Campello C, Bouly S, Le Floch A, Thouvenot E, et al. An MRI review of acquired corpus callosum lesions. J Neurol Neurosurg Psychiatry. 2014;85(9):1041–8.View ArticlePubMedGoogle Scholar
- Tada H, Takanashi J, Barkovich AJ, Oba H, Maeda M, Tsukahara H, et al. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion. Neurology. 2004;63(10):1854–8.View ArticlePubMedGoogle Scholar
- Takanashi J, Barkovich AJ, Shiihara T, Tada H, Kawatani M, Tsukahara H, et al. Widening spectrum of a reversible splenial lesion with transiently reduced diffusion. AJNR Am J Neuroradiol. 2006;27(4):836–8.PubMedGoogle Scholar
- Takanashi J, Tada H, Maeda M, Suzuki M, Terada H, Barkovich AJ. Encephalopathy with a reversible splenial lesion is associated with hyponatremia. Brain Dev. 2009;31(3):217–20.View ArticlePubMedGoogle Scholar
- Kometani H, Kawatani M, Ohta G, Okazaki S, Ogura K, Yasutomi M, et al. Marked elevation of interleukin-6 in mild encephalopathy with a reversible splenial lesion (MERS) associated with acute focal bacterial nephritis caused by Enterococcus faecalis. Brain Dev. 2014;36(6):551–3.View ArticlePubMedGoogle Scholar
- Morichi S, Kawashima H, Ioi H, Yamanaka G, Kashiwagi Y, Hoshika A. High production of interleukin-10 and interferon-gamma in influenza-associated MERS in the early phase. Pediatr Int. 2012;54(4):536–8.View ArticlePubMedGoogle Scholar
- Kaneko T, Wada H. Diagnostic criteria and laboratory tests for disseminated intravascular coagulation. J Clin Exp Hematop. 2011;51(2):67–76.View ArticlePubMedGoogle Scholar
- Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31.View ArticlePubMedGoogle Scholar
- Takahashi T, Maeda K, Suzuki T, Ishido A, Shigeoka T, Tominaga T, et al. The first identification and retrospective study of Severe Fever with Thrombocytopenia Syndrome in Japan. J Infect Dis. 2014;209(6):816–27.View ArticlePubMedGoogle Scholar
- Yoshikawa T, Fukushi S, Tani H, Fukuma A, Taniguchi S, Toda S, et al. Sensitive and specific PCR systems for detection of both Chinese and Japanese severe fever with thrombocytopenia syndrome virus strains and prediction of patient survival based on viral load. J Clin Microbiol. 2014;52(9):3325–33.View ArticlePubMedPubMed CentralGoogle Scholar
- Ka A, Britton P, Troedson C, Webster R, Procopis P, Ging J, et al. Mild encephalopathy with reversible splenial lesion: an important differential of encephalitis. Eur J Paediatr Neurol. 2015;19(3):377–82.View ArticlePubMedGoogle Scholar
- Takanashi J, Imamura A, Hayakawa F, Terada H. Differences in the time course of splenial and white matter lesions in clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). J Neurol Sci. 2010;292(1-2):24–7.View ArticlePubMedGoogle Scholar
- Cui N, Liu R, Lu QB, Wang LY, Qin SL, Yang ZD, et al. Severe fever with thrombocytopenia syndrome bunyavirus-related human encephalitis. J Infect. 2015;70(1):52–9.View ArticlePubMedGoogle Scholar
- Achalia R, Andrade C. Reversible abnormality of the splenium in a bipolar patient with neuroleptic malignant syndrome. Bipolar Disord. 2014;16(7):773–5.View ArticlePubMedGoogle Scholar
- Deng B, Zhou B, Zhang S, Zhu Y, Han L, Geng Y, et al. Clinical features and factors associated with severity and fatality among patients with severe fever with thrombocytopenia syndrome Bunyavirus infection in Northeast China. PLoS One. 2013;8(11):e80802.View ArticlePubMedPubMed CentralGoogle Scholar
- Zhang YZ, He YW, Dai YA, Xiong Y, Zheng H, Zhou DJ, et al. Hemorrhagic fever caused by a novel Bunyavirus in China: pathogenesis and correlates of fatal outcome. Clin Infect Dis. 2012;54(4):527–33.View ArticlePubMedGoogle Scholar
- Sun L, Hu Y, Niyonsaba A, Tong Q, Lu L, Li H, et al. Detection and evaluation of immunofunction of patients with severe fever with thrombocytopenia syndrome. Clin Exp Med. 2014;14(4):389–95.View ArticlePubMedGoogle Scholar
- Weng Y, Chen N, Han Y, Xing Y, Li J. Clinical and laboratory characteristics of severe fever with thrombocytopenia syndrome in Chinese patients. Braz J Infect Dis. 2014;18(1):88–91.View ArticlePubMedGoogle Scholar
- Hiraki T, Yoshimitsu M, Suzuki T, Goto Y, Higashi M, Yokoyama S, et al. Two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) in Japan: a pathognomonic histological feature and unique complication of SFTS. Pathol Int. 2014;64(11):569–75.View ArticlePubMedPubMed CentralGoogle Scholar
- Liu Q, He B, Huang SY, Wei F, Zhu XQ. Severe fever with thrombocytopenia syndrome, an emerging tick-borne zoonosis. Lancet Infect Dis. 2014;14(8):763–72.View ArticlePubMedGoogle Scholar